What is phenylketonuria?

Phenylketonuria (PKU) is a rare, inherited disorder. The body of a person born with PKU is unable to break down phenylalanine, an amino acid,  which is an important substance in human metabolism. As a result, phenylalanine accumulates in the body and can lead to the person developing an intellectual disability. PKU in a pregnant woman can also lead to the baby developing an intellectual disability.

A blood test for newborn babies ('heel prick test') done in the days after birth is effective at screening for PKU. A special diet can prevent the harmful effects of the condition.

PKU appears in about one in every 10,000 newborn babies and there are about 50,000 people living with the condition in the world. [1] [2]  The occurrence of PKU varies among populations - in Turkey, the condition appears in one of 2,600 births; in most people of European and South-East Asian descent, including Caucasian Americans and Canadians, Koreans and most Chinese, PKU appears in one of 10,000-15,000 babies born, and it is less common in many other populations, including African-Americans, Africans and Japanese. [2]

Since the introduction of a genetic test for PKU, the number of people showing symptoms has dropped significantly.

1. Hardelid P. Cortina-Borja M. Munro A. et al. (2008) The birth prevalence of PKU in populations of European South Asian and Sub-Saharan African ancestry living in South East England. Annals of Human Genetics 72:65–71.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

Causes

All proteins are composed of amino acids. There are 22 standard amino acids that, in multiple different combinations, form all the kinds of proteins in a human body and in other living organisms, including the plants and animals we eat.

Phenylalanine is one of the 22 amino acids and is found in varying degrees in nearly all kinds of proteins in our food. The human body cannot manufacture phenylalanine, so it must get this amino acid from food.

A gene in our DNA contains the instructions for the body to manufacture an enzyme called phenylalanine hydroxylase (PAH). This enzyme operates in the liver and the kidneys, and converts phenylalanine into tyrosine, another type of amino acid.

People who have a faulty version of the phenylalanine (PAH) gene cannot manufacture the PAH enzyme and therefore cannot break down phenylalanine. As a result, this amino acid accumulates in the body and causes damage to nerve cells in the body, especially the brain.

The PAH enzyme operates in the liver and kidneys, and breaks down the amino acid phenylalanine. In people with phenylketonuria, the PAH enzyme is defective, and phenylalanine accumulates in the body. 

PKU is a recessive autosomal disorder. In these disorders, the affected person receives two faulty versions of the gene, one copy from each parent. If the person receives one faulty allele and one working allele, that person is a healthy carrier of the gene. Healthy carriers do not suffer from the disorder, but can pass on the faulty allele to their offspring.

Healthy parents, who are carriers of faulty PAH gene, can have children who are either unaffected, carriers or develop PKU.Phenylketonuria causes a toxic build-up of phenylalanine. 

Several mutations can affect the PAH gene. Some of these mutations result in a PAH enzyme that is faulty but partially active, resulting in a milder form of PKU. Other mutations render the PAH enzyme completely useless, resulting in 'classic' PKU, a severe disorder.

Amino acids

A large organic molecule that is the basic building block of proteins. There are 20 amino acids used by the human body that link together, in various orders, to form proteins.

DNA

The genetic material of all living cells and some viruses. The full name is deoxyribonucleic acid.

Enzyme

Molecules (mainly proteins) produced by cells that can drive specific chemical reactions.

Mutations

An inheritable change in the base sequence of the genome of an organism.

1. Hardelid P. Cortina-Borja M. Munro A. et al. (2008) The birth prevalence of PKU in populations of European South Asian and Sub-Saharan African ancestry living in South East England. Annals of Human Genetics 72:65–71.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

Risk factors

PKU is strictly an inherited disease. People at risk of being born with it are people whose parents have a faulty PAH allele.

1. Hardelid P. Cortina-Borja M. Munro A. et al. (2008) The birth prevalence of PKU in populations of European South Asian and Sub-Saharan African ancestry living in South East England. Annals of Human Genetics 72:65–71.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

Types

As mentioned above, the PAH gene can be completely or partially faulty. Thus, PKU can also be classified as severe, moderate or mild.

1. Hardelid P. Cortina-Borja M. Munro A. et al. (2008) The birth prevalence of PKU in populations of European South Asian and Sub-Saharan African ancestry living in South East England. Annals of Human Genetics 72:65–71.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

Signs and symptoms

Babies born with PKU show no symptoms at birth. If PKU is not detected and/or the recommended diet is not followed within a few weeks after birth, symptoms will gradually start to appear, as phenylalanine starts accumulating.

The most profound symptom of PKU is intellectual disability. This can be mild to severe according to the severity of the genetic disorder. Problems can include:

Other symptoms that can appear as phenylalanine accumulates in the child's body include:

  • An unusually small head (microcephaly);
  • Jerky movements, trembling and seizures;
  • A distinctive musty smell of the body, breath and urine;
  • Recurrent vomiting;
  • Eczema, and;
  • Light-colored skin, fair hair, and light-colored (often blue) eyes.

Children and adults with PKU who stick to their diet are generally fine and function normally throughout their lifetime.

There are indications that adults with PKU might have a somewhat higher chance of developing certain mental health problems, such as depression and anxiety, and some minor problems with cognitive skills such as planning.

PKU and pregnancy

A woman with PKU can, if she does not follow the diet, cause severe problems for her offspring. The phenylalanine in her blood can affect the fetus' development in the womb and cause it to have severe cognitive problems.

Cognitive

Relating to cognition, which are the mental processes and abilities associated with acts of judgement, reasoning and understanding.

1. Hardelid P. Cortina-Borja M. Munro A. et al. (2008) The birth prevalence of PKU in populations of European South Asian and Sub-Saharan African ancestry living in South East England. Annals of Human Genetics 72:65–71.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

Methods for diagnosis

A blood test for PKU is performed on all newborn babies. If the result is positive, further blood tests and urine tests are done to confirm the diagnosis.

1. Hardelid P. Cortina-Borja M. Munro A. et al. (2008) The birth prevalence of PKU in populations of European South Asian and Sub-Saharan African ancestry living in South East England. Annals of Human Genetics 72:65–71.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

Types of treatment

The only treatment for PKU is a special diet low in phenylalanine that must be followed for life. The diet is not easy to follow, as it is quite strict and requires effort and discipline. In milder cases of PKU, a measure of leeway is sometimes possible. A person with PKU will normally undergo regular testing for phenylalanine levels. The test results will inform about the compliance with the special diet.

It is particularly important for women to follow the diet strictly before and during pregnancy, as the phenylalanine that accumulates in their bodies will cause profound harm to their unborn baby.

Future treatment prospects

In the future, gene therapy may be able to cure PKU. This, however, is still some way off.

An enzyme, PEGylated recombinant phenylalanine ammonia lyase (PEG-PAL), which may replace PAH and break down phenylalanine in the body has been in development for some years and is showing promise, but is still not approved for use at this time.

Enzyme

Molecules (mainly proteins) produced by cells that can drive specific chemical reactions.

1. Hardelid P. Cortina-Borja M. Munro A. et al. (2008) The birth prevalence of PKU in populations of European South Asian and Sub-Saharan African ancestry living in South East England. Annals of Human Genetics 72:65–71.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

Prognosis

If PKU is diagnosed and managed properly (i.e. the diet is followed, which is not an easy diet to follow) then you can live with PKU with no ill effects.

1. Hardelid P. Cortina-Borja M. Munro A. et al. (2008) The birth prevalence of PKU in populations of European South Asian and Sub-Saharan African ancestry living in South East England. Annals of Human Genetics 72:65–71.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

Prevention

People who have a family history of PKU can consider genetic counselling before attempting to conceive babies, to assess their chances of having children with PKU.

Women with PKU can prevent birth defects in their babies by adhering to the restricted diet before and during pregnancy.

Genetic counselling

A service in which a specialist in genetics provides information and resources regarding genetic conditions. A genetic counsellor uses medical records, family history and screening tests to evaluate the likelihood of a person passing down or inheriting a genetic condition.

1. Hardelid P. Cortina-Borja M. Munro A. et al. (2008) The birth prevalence of PKU in populations of European South Asian and Sub-Saharan African ancestry living in South East England. Annals of Human Genetics 72:65–71.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.

2. van Spronsen F.J. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:509-514.